Inducible expression of defensins and cathelicidins by nutrients and associated regulatory mechanisms

Highlights

• Some nutrients are able to induce the expression of endogenous defensins and cathelicidins.

• The MAPK, NF-κB and HDAC signaling pathways play vital roles in the induction of defensin and cathelicidin expression.

• Defensin and cathelicidin-inducing nutrients have potential applications in disease control and prevention.

Abstract

Host defense peptides (HDPs) are crucial components of the body's first line of defense that protect organisms from infections and mediate immune responses. Defensins and cathelicidins are the two most important families of HDPs in mammals. In this review, we summarize the nutrients that are involved in inducible expression of endogenous defensins and cathelicidins. In addition, the mitogen-activated protein kinases (MAPK), nuclear factor kappa B (NF-κB) and histone deacetylase (HDAC) signaling pathways that play vital roles in the induction of defensin and cathelicidin expression are highlighted. Endogenous defensins and cathelicidins induced by nutrients may be potential alternatives to antibiotic treatments against infection and diseases. This review mainly focuses on the inducible expression and regulatory mechanisms of defensins and cathelicidins in multiple species by different nutrients and the potential applications of defensin- and cathelicidin-inducing nutrients.

Introduction

The innate immune system is the body's first line of defense, and is important in preventing microbes from infecting living organisms. Host defense peptides (HDPs), also known as antimicrobial peptides, play a key role in the innate immune system, and are found in nearly all forms of life, including bacteria, fungi, plants, insects, birds, crustaceans, amphibians and mammals [[1], [2], [3]]. HDPs consist of amino acids that are rich in cationic residues and are mainly amphipathic, varying in size from five to over a hundred amino acids [4]. In mammals, most HDPs are expressed on mucosal surfaces of the respiratory, gastrointestinal or urogenital system and have a pleiotropic effect on innate adaptive immune responses [5]. These peptides can kill bacteria (gram-positive or gram-negative), protozoa, parasites, viruses or fungi. In addition, many HDPs have a profound impact on the regulation of inflammation, wound healing and adaptive immunity [[6], [7], [8]]. HDPs include defensins, cathelicidins, C-type lectins and S100 proteins, in which defensins and cathelicidins are the two major families [[9], [10], [11]]. Defensins are nonglycosylated peptides that can be classified into three subfamilies: α-defensins, which are found in most mammals; β-defensins, which are present in all vertebrate animals; and θ-defensins, which only exist in primates [12]. Cathelicidins contain a highly conserved domain with an analogue to that of cathelin, a porcine cysteine-protease inhibitor [13,14], and provide early and broad-spectrum antimicrobial protection at epithelial cell surface [15].

Defensins and cathelicidins are cationic antimicrobial peptides with an overall net positive charge [7]. There are distinct differences between eukaryotic and prokaryotic cell membrane properties. The eukaryotic cell membrane is largely uncharged with a high cholesterol content and low transmembrane potential of approximately −15 mV. However, the prokaryotic cell membrane is severely negatively charged with a high transmembrane potential (−140 mV) [16]. Microbes are killed by defensins and cathelicidins mainly via physical disruption of membranes or nonspecific inhibition of cellular transcription and translation [7], unlike the mechanisms by which antibiotics inhibit the synthesis of bacterial cell walls, DNA or proteins [4]. As these hypotheses describe, fatal depolarization of the normally energized bacterial membrane or the creation of physical holes causes cellular contents to leak out, which kills the microbes [7,17]. Such unique and nonspecific mechanisms enable HDPs to avoid the common resistance mechanisms of conventional antibiotics [18]. HDPs induce little resistance, which makes them promising alternative candidates to antibiotics.

The exogenous addition of HDPs such as cecropin A has been shown to alleviate inflammation in inflammatory bowel disease in mice and enhance the barrier function of intestinal epithelial cells [19,20]. However, because of the high cost of chemical synthesis of exogenous HDPs, inducible expression of endogenous HDPs seems to be a more economical solution. It has been reported that the expression of endogenous HDPs can be induced by infection, inflammatory mediators, bacteria and cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-1β [[21], [22], [23], [24]]. However, it is not desirable to induce HDPs by infection and inflammation due to an excessive inflammatory response. Recently, studies have demonstrated that HDPs can be induced by nutrients without provoking an inflammatory response, which is promising for preventing infection and controlling disease [25]. This review will describe the inducible expression of endogenous HDPs by nutrients, such as amino acids, fatty acids, carbohydrates, vitamins and plant extracts, as well as their regulatory mechanisms, for a better understanding of HDP-inducing nutrients and their potential applications.